At least 4 iron-overload disorders labeled hemochromatosis have been identified on the basis of clinical, biochemical, and genetic characteristics. Hemochromatosis type 1 is classic hemochromatosis (sometimes designated “HFE”) (see OMIM Number: 235200; Online Mendelian Inheritance in Man, OMIM™. Johns Hopkins University, Baltimore, Md., at www.ncbi.nlm.nih.gov/omim/), an autosomal recessive disorder, which is caused by mutation in a gene designated HFE on chromosome 6p21.3. The medical disorder called juvenile hemochromatosis (sometimes called “JH” or “juvenile haemochromatosis”), is also known as hemochromatosis type 2 (“HFE2”). Hemochromatosis type 3 (HFE3; OMIM 604250), an autosomal recessive disorder, is caused by mutation in the gene encoding transferrin receptor-2 (TFR2; OMIM 604720), which maps to 7q22. Hemochromatosis type 4 (HFE4; OMIM 606069), an autosomal dominant disorder, is caused by mutation in the SLC11A3 gene (OMIM 604653), which encodes ferroportin and maps to 2q32.
In some families juvenile hemochromatosis shows linkage to chromosome 1q21, whereas in others it is caused by mutation in the gene encoding hepcidin antimicrobial peptide, which maps to chromosome 19q13.
The two forms of juvenile hemochromatosis (HFE2) are tentatively designated HFE2A and HFE2B, respectively. The present invention relates to the genetic basis of HFE2A, the form of JH linked to chromosome 1q21.
Juvenile hemochromatosis (JH) differs from typical hereditary hemochromatosis. While HFE has a prevalent male expression, JH affects both sexes equally. JH involves iron accumulation, which begins early in life and typically causes clinical symptoms before the age of 30 years. JH is a more severe disease than typical hereditary hemochomotosis, with JH showing hypogonadotropic hypogonadism, heart failure, arrhythmias and/or cardiomyopathy as frequent features. If untreated, the disease is lethal because of cardiac and other complications.
Identification of 1q21 as the chromosomal location of HFE2A was first reported in Roetto et al., Am. J. Hum. Genet. 64:1388-1393 (1999) but this locus did not correspond to the chromosomal location of any known gene involved in iron metabolism.
The present invention provides identification of the hereditary basis for HFE2A, thereby facilitating development of more potent agents for treating diseases of iron metabolism. Administration of the HFE2A gene or protein itself may be therapeutic. Alternatively, the underlying genetic mutation identifies a novel therapeutic target for treating diseases of iron metabolism. This therapeutic target can be used to identify and discover more effective therapeutic agents. Diagnostic compounds, kits and methods using HFE2A are also included which may be used to diagnose JH as well as to diagnose and predict onset and severity of adult hemochromatosis and to distinguish between types of iron metabolism disorders.